The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo

Vascular endothelial growth factor (VEGF) is known to occur as at least six differentially spliced variants, giving rise to mature isoforms containing 121, 145, 165, 183, 189 and 206 amino acids. However, little is yet known concerning the in vivo activities of this differential splicing. Stably transfected MCF-7 breast carcinoma cells were constructed that secreted comparable amounts of the 121, 165 or 189 isoforms. Rabbit corneal angiogenesis assays showed the VEGF121 transfectant to have much greater angiogenic activity than the 165 or 189 expressing MCF-7 cells. While the VEGF121-expressing MCF-7 cells were reproducibly more tumorigenic than the control transfectants, this was not the case with the VEGF165- or VEGF189-expressing cells. More surprising was the observation that VEGF189 located to the nucleus, consistent with the presence of a highly conserved nuclear localization sequence in exon 6a that is expressed in VEGF189 but not 121 or 165. It was concluded that the VEGF121 isoform is both more angiogenic and tumorigenic than are the 165 and 189 isoforms. This is probably due to the ability of the 121 isoform, unlike the 165 and 189 isoforms, to freely diffuse from the cells producing it. © 2000 Cancer Research Campaign

[1]  J. Folkman,et al.  Tumor growth and neovascularization: an experimental model using the rabbit cornea. , 1974, Journal of the National Cancer Institute.

[2]  G. Peters,et al.  Subcellular fate of the lnt-2 oncoprotein is determined by choice of initiation codon , 1990, Nature.

[3]  J. Winer,et al.  The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. , 1991, Molecular endocrinology.

[4]  J. Fiddes,et al.  The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. , 1991, The Journal of biological chemistry.

[5]  R. Laskey,et al.  Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: Identification of a class of bipartite nuclear targeting sequence , 1991, Cell.

[6]  J. Winer,et al.  Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. , 1992, The Journal of biological chemistry.

[7]  J. Park,et al.  The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. , 1993, Molecular biology of the cell.

[8]  A. Harris,et al.  Topoisomerase II alpha co-amplification with erbB2 in human primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitoxantrone sensitivity. , 1993, Oncogene.

[9]  T. Bader,et al.  Nuclear accumulation of interferon gamma. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[10]  S Amerini,et al.  Nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. , 1994, The Journal of clinical investigation.

[11]  M. Ziche,et al.  Growth advantage and vascularization induced by basic fibroblast growth factor overexpression in endometrial HEC-1-B cells: an export-dependent mechanism of action. , 1995, Cancer research.

[12]  A. Harris,et al.  Enhancement of tumor growth and vascular density by transfection of vascular endothelial cell growth factor into MCF-7 human breast carcinoma cells. , 1995, Journal of the National Cancer Institute.

[13]  M. Klagsbrun,et al.  Vascular endothelial growth factor and its receptors. , 1996, Cytokine & growth factor reviews.

[14]  Hung V. Nguyen,et al.  The Carboxyl-terminal Domain(111165) of Vascular Endothelial Growth Factor Is Critical for Its Mitogenic Potency (*) , 1996, The Journal of Biological Chemistry.

[15]  S. Soker,et al.  Selective binding of VEGF121 to one of the three vascular endothelial growth factor receptors of vascular endothelial cells. , 1996, The Journal of biological chemistry.

[16]  G. Martiny-Baron,et al.  Expression of biologically active isoforms of the tumor angiogenesis factor VEGF in Escherichia coli. , 1996, Biochemical and biophysical research communications.

[17]  R Bicknell,et al.  Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. , 1997, The Journal of clinical investigation.

[18]  S. Fox,et al.  Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenes , 1997, Cancer research.

[19]  A. Harris,et al.  Expression of VEGF in routinely fixed material using a new monoclonal , 1998, The Journal of pathology.

[20]  P. Welker,et al.  Synthesis, storage, and release of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by human mast cells: implications for the biological significance of VEGF206. , 1998, Molecular biology of the cell.

[21]  S. Leung,et al.  Tissue-specific expression pattern of vascular endothelial growth factor isoforms in the malignant transformation of lung and colon. , 1998, Human pathology.

[22]  Jianxun Lei,et al.  Identification and characterization of a new splicing variant of vascular endothelial growth factor: VEGF183. , 1998, Biochimica et biophysica acta.

[23]  Willem Flameng,et al.  Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188 , 1999, Nature Medicine.

[24]  G. Neufeld,et al.  Vascular endothelial growth factor (VEGF) and its receptors , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.